Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:18])[N:14]=[CH:15][C:16](I)=[C:11]2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:25](=[O:27])=[O:26]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:18])=[N:14][CH:15]=[C:16]([C:25]([OH:27])=[O:26])[C:11]=2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(I)c12
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12

Procedure:
To a solution of 7-chloro-4-iodo-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (200 mg) in dry tetrahydrofuran (4 ml) at −40° C. under an atmosphere of nitrogen, was added dropwise, a solution of isopropylmagnesium chloride (2M in tetrahydrofuran, 600 ul) and the solution stirred at −40° C. for 15 minutes. The solution was saturated with a stream of carbon dioxide gas and then diluted with ethyl acetate. The organic was extracted with saturated ammonium chloride followed by 1N sodium hydroxide solution. The combined aqueous was then acidified to pH1 with concentrated hydrochloric acid to afford a precipitate. The precipitate was filtered and washed with water until neutral. The solid was then sucked dry and dried over sodium hydroxide at 50° C. to afford the title compound (86 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O.CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
10 g (50.6 mmol) of 6-chloroisatoic acid anhydride are stirred at 110° C. for 2 hours with 5.82 g (50.6 mmol) of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallised from ethyl acetate. There is obtained (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 264°-266° C. (b) A solution of 4.0 g (16 mmol) of (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10)-dione in 30 ml of dimethylformamide is treated under an argon atmosphere with 0.57 g (16 mmol) of sodium hydride (60 percent oil dispersion) and stirred at room temperature for 1 hour. 3.02 g (17.5 mmol) of diethylchlorophosphate are added dropwise to the thus-obtained suspension at -20° C. and the mixture is stirred at this temperature for 10 minutes.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([C@H:8]2[CH2:11][C@@H:10]([CH2:12][O:13]CC3C=CC=CC=3)[CH2:9]2)[CH:7]=1.C(O)=O.[H][H]>[Pd].C(O)C>[F:1][C:2]1[C:3](=[O:22])[NH:4][C:5](=[O:21])[N:6]([C@H:8]2[CH2:9][C@@H:10]([CH2:12][OH:13])[CH2:11]2)[CH:7]=1
Reactant: [H][H]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@@H](COCc3ccccc3)C2)cc1F
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: O=c1[nH]c(=O)n([C@H]2C[C@@H](CO)C2)cc1F

Procedure:
A solution of 5-fluoro-1-[cis-3-(benzyloxymethyl)cyclobutyl]uracil (250 mg, 0.79 mmol), 10% palladium on activated carbon (50 mg) and formic acid (2 mL) in ethanol (20 mL) was placed under 45 PSI of hydrogen on a Parr Apparatus for 2 h. The mixture was filtered through a pad of Celite and the charcoal was washed with ethanol (3×20 mL). Combined filtrates were concentrated under vacuum and purified by a short column of silica gel with 4% MeOH in CH2Cl2 to give 5-fluoro-1-[cis-3-(hydroxymethyl)cyclobutyl]uracil (159 mg, 94%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:1][CH3:2])[CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc(O)c2cccc(OC)c2n1
Solvent: CN(C)c1ccccc1
Product: CCc1cc(Cl)c2cccc(OC)c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-ethyl-4-hydroxy-8-methoxyquinoline (9.96 g) in phosphoryl chloride (30 ml) was added N,N-dimethylaniline (12.44 ml) below 8° C. in an ice bath. After 10 minutes the mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo. The residue was partitioned into dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. The organic layer was evaporated in vacuo. The residue was purified by column chromatography (hexane--ethyl acetate) and recrystallized from hexane to give 4-chloro-2-ethyl-8-methoxyquinoline (8.90 g) as crystals. mp: 80-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:25]([C:24]4[CH:28]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=4[N:29]4[N:33]=[CH:32][CH:31]=[N:30]4)=[O:26])[CH2:16]3)[CH2:12]2)[N:4]=1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and Intermediate 1. MS (ESI) mass calcd. for C22H22FN7O3, 439.18; m/z found, 440.1 [M+H]+. 1H NMR (CDCl3): 7.89 (dd, J=8.9, 4.7 Hz, 1H), 7.66 (s, 1H), 7.25-7.01 (m, 2H), 5.32 (s, 1H), 3.77 (m, 8H), 3.67-3.54 (m, 2H), 3.52-3.26 (m, 3H), 3.01-2.78 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([NH2:13])[NH:4][N:3]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CS(O)(=O)=O>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:19]([C:18]3[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=3)=[N:13][C:5]=2[NH:4][N:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1n[nH]c(N)c1-c1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)c3ccccc3c12
Temperature: 120 °C
Yield: 15 %

Procedure:
To 3-methyl-4-phenyl-1H-pyrazol-5-amine (173 mg, 1 mmol) was added 4-hydroxybezaldehyde (244 mg, 2 mmol) and methanesulfonic acid (3 mL). The mixture was heated to 120° C. for 16 h. After cooling to rt, the mixture was diluted with ethyl acetate and then filtered through celite. The product was then extracted from the organic phase with NaOH (aq). The organic phase was discarded, and the aqueous extract was carefully neutralized with HCl (conc) and then extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (ethyl acetate) to provide 41.2 mg of 4-(1-methyl-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol (0.15 mmol, 15% yield). 1H-NMR (400 MHz, DMSO-d6): δ13.42 (s, 1H), 9.81 (s, 1H), 8.34 (d, 1H), 8.11 (d, 1H), 7.87 (t, 1H), 7.50 (d, 2H), 6.94 (d, 2H), 2.79 (s, 3H); MS (EI) for C17H13N3O: 276 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[C:49](=[O:50])[C:48]([C:51](O)=[O:52])=[CH:47][CH:46]=[N:45]2)=[CH:40][CH:39]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:34][N:32]([CH3:33])[CH:29]1[CH2:30][CH2:31][N:26]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:51]([C:48]4[C:49](=[O:50])[N:44]([C:41]5[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=5)[N:45]=[CH:46][CH:47]=4)=[O:52])=[CH:20][C:19]=3[F:25])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)[N:9]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine (35.8 mg, 0.07298 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (25.63 mg, 0.1095 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (69.95 mg, 0.3649 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (49.30 mg, 0.3649 mmol), N-ethyl-N-isopropylpropan-2-amine (47.16 mg, 0.3649 mmol) and DMF (5 mL). The reaction mixture was stirred at room temperature overnight. Then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (33.1 mg, 64.18%). LRMS (APCI pos): m/e 707 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[C:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([N:11]=[C:12]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(Cl)(Cl)Cl>[C:18]([NH:17][C:12]1[S:13][CH2:14][C@@H:15]2[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@:10]2([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:11]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CSC(NC(=O)c3ccccc3)=NC2(c2ccccc2)C1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccccc2)C1

Procedure:
Racemic tert-butyl-2-benzamido-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.6 g, 3.66 mmol) is dissolved in ethanol/chloroform (30 ml/14 ml) and is separated into its constituent enantiomers by chiral SFC (Supercritical Fluid Chromatography) (Chiralpak AD 8×40.5 cm (20 μm); eluent: 100% ethanol in CO2; flow: 350 mL/min at UV 280 nm; 0.4 g/injection). The first eluting isomer is the title compound (593 mg, 37%). Chiral analysis of this isomer: (Chiralpak AD-H 4.6×150 mm; eluent: 100% ethanol with 0.2% isopropyl amine) in CO2; flow 1 mL/min at UV 225 nm) Rt=3.03 to (>98% ee). ES/MS (m/e): 438 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)[CH3:3].Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:20]N)[CH:17]=[CH:18][CH:19]=1.Cl>C(O)C>[CH3:1][N:2]([CH3:3])[CH:4]1[CH2:9][C:8]2[C:17]3[C:16](=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=3)[NH:20][C:7]=2[CH2:6][CH2:5]1
Reactant: CN(C)C1CCCCC1=O
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c3c([nH]c2c1)CCC(N(C)C)C3

Procedure:
A solution of 7 g. of dimethylaminocyclohexanone and 8.4 g. of 3-methoxyphenylhydrazine hydrochloride in 40 ml. of absolute ethyl alcohol and 12 ml. of 4-N hydrogen chloride in ethyl alcohol was heated under reflux for two hours. The reaction mixture was allowed to stand for sixteen hours, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in water, made alkaline with dilute sodium hydroxide and extracted with ether. The ether extract was washed with water, dried, ethereal hydrogen chloride was added, and the resulting oily precipitate was collected by decantation, recrystallized twice from isopropyl alcohol, suspended in chloroform and treated with dilute sodium hydroxide. The chloroform extract was evaporated to dryness under reduced pressure to give 3-(dimethylamino)-7-methoxy-1,2,3,4-tetrahydrocarbazole, m.p. 100°-105° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[C:28]([C:29]([C:31]5([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:31]1([C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)[N:21]=3)[NH:26][CH:27]=2)=[O:30])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc(N5CCNCC5)cc4)nc23)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A solution of 4-{4-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (35 mg, 0.069 mmol) in DCM (5 ml), at 0° C., was treated with TFA (0.15 ml, 2.01 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then refluxed for 1.5 hours. The reaction mixture was concentrated to dryness, and the resulting residue was partitioned between sat. NaHCO3 and EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated providing 25 mg (89%) of (1-methyl-cyclohexyl)-[2-(4-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a yellow solid. MP 214-216° C., M+H=404.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O.[O-:27][CH2:28][CH3:29].[Na+].C(O)C>C(OCC)(=O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH:25]([C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[C:28](=[O:27])[C:29]3[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7]2)=[CH:18][CH:19]=1
Reactant: CC[O-]
Reactant: O=Cc1nccs1
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccs1)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (1.88 g, 7.37 mmol) and thiazole-2-carbaldehyde (1 g, 8.8 mmol) in ethyl propionate (50 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (678 g, 29 mmol) in ethanol (30 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10) to give the crude compound (180 mg). LC-MS (ESI) m/z: 397 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([NH:46][C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Reactant: CC(C)(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NC(C)(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A solution of Example C2 (0.100 g, 0.238 mmol) in DCM (5 mL) was treated with mCPBA (0.059 g, 0.238 mmol), stirred at RT for 2 h, treated with t-butylamine (0.4 mL, 3.81 mmol) and stirred at RT overnight. Additional t-butylamine (0.4 mL, 3.81 mmol) was added and the mixture stirred at RT for an additional 24 h. The mixture was concentrated to dryness, transferred to a sealed vessel with DMF (5 mL), treated with additional t-butylamine (0.4 mL, 3.81 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, the solids removed via filtration and washed with DCM. The filtrate was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were washed with 5% LiCl (3×), then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(tert-butyl)-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (69 mg, 65%). MS (ESI) m/z: 446.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:38][O:39][C:40]([NH:42][CH:43]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:44](=[O:45])[CH:43]([NH:42][C:40]([O:39][CH3:38])=[O:41])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of 1-{[4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (600 mg, 1.115 mmol) in CH3CN (20 mL) was 2-methoxycarbonylamino-3,3-dimethyl-butyric acid (317 mg, 1.673 mmol), DIEA (0.97 mL, 5.575 mmol) and the coupling reagent HOBt (256 mg, 1.673 nunol) and HBTU (634 g, 1.673 mmol). The solution was stirred at rt. overnight. Then it was concentrated, washed with water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give yellowish oil. It was then purified by Prep. HPLC column to give a yellowish oil as product. (410 mg, 47% yield).1H NMR (400 MHz, CD3OD) δ1.03 (s, 9H), 1.22 (t, J=7.09 Hz, 3H), 1.41 (dd, J=9.41, 5.26 Hz, 1H), 1.71 (dd, J=8.19, 5.26 Hz, 1H), 2.17 (m, 1H), 2.50 (m, 1H), 2.77 (m, 1H), 3.33 (s, 3H), 4.03 (s, 3H), 4.04–4.14 (m, 3H), 4.18 (s, 1H), 4.61–4.69 (m, 2H), 4.86 (m, 1H), 5.08 (dd, J=10.27, 1.71 Hz, 1H), 5.25 (d, J=17.11 Hz, 1H), 5.72–5.82 (m, 2H), 7.39 (dd, J=9.29, 2.20 Hz, 1H), 7.51 (m, 1H), 7.63 (m, 1H), 7.69–7.77 (m, 3H), 8.06 (m, 2H), 8.35 (d, J=9.29 Hz, 1H), 8.75 (s, 1H). LC-MS (retention time: 2.857 min.), MS m/z 673 (MH+).
Reaction SMILES: [AlH4-].[Li+].O1CCCC1.[CH2:8]([N:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:15]=2[N:14]=[N:13]1)[CH2:9][CH2:10][CH3:11]>O>[CH2:8]([N:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][OH:22])=[CH:20][C:15]=2[N:14]=[N:13]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1nnc2cc(C(=O)O)ccc21
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1nnc2cc(CO)ccc21
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a stirred and cooled (0° C.) suspension of 23.4 parts of lithium tetrahydroaluminate in 270 parts of dry tetrahydrofuran were added portionwise 45 parts of 1-butyl-1H-benzotriazole-5-carboxylic acid. Upon complete addition, stirring was continued for 1 hour at 0° C. The reaction mixture was hydrolysed with 50 parts of water. The whole was filtered and washed with a mixture of dichloromethane and methanol (90:10 by volume). The filtrate was evaporated to dry and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (42.7%) of 1-butyl-1H-benzotriazole-5-methanol as an oily residue (int. 10).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:1][CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
To a 1-L round-bottom flask equipped with a magnetic stir-bar and a N2 inlet was added Ethyl 4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate (42 g, 0.127 moles, 1 eq) and dry CH2Cl2 (300 ml) at room temperature. This was followed by the addition of 3,4-dihydro-2H-pyran (14 ml, 0.152 moles, 1.2 eq) as a neat liquid and pyridinium p-toluenesulfonate (6.4 g, 25.4 mmoles, 20 mol %). The reaction mixture was stirred at room temperature overnight (10 hrs). The volatiles were then removed in vacuo and the residue was purified by flash silica gel chromatography (10% EtOAc/Hexanes to 30% EtOAc/Hexanes) to yield 34 g (64%) of pure title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]([CH3:39])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and benzyl-methyl-amine. MS (ESI): 462.4 (MH+).